Diseases caused by excessive, uncontrolled cell proliferation account for thousands of life threatening diseases diagnosed each year. Cell proliferative diseases include the various cancers as well as diseases whose etiology has only recently been correlated with cell proliferation. Particular examples include astrocyte proliferation in the brains of AIDS dementia patients, atherosclerosis, glomerulosclerosis resulting from retroviral-induced renal disease.
Lymphomas are a common form of cancer in HIV-infected patients. Of the approximately 36,000 new cases of lymphoma diagnosed in the United States in 1992, between 8 and 27% are estimated to have occurred in HIV-infected individuals (Gail, M. H. et al., J Natl Can Int (1991) 83:695-701). Thus, HIV-related lymphoma represents a major clinical problem for physicians involved in the care of HIV-infected individuals.
The biology of AIDS lymphoma is controversial and appears complex. Early in the AIDS epidemic high grade non-Hodgkin's lymphoma (NHL) began to appear in individuals at risk for the development of AIDS (Ziegler, J. et al., N Eng J Med (1984) 311:565-570). However, in the past several years, the incidence of NHL in HIV-infected individuals has increased (Harnly, M. E. et al., Am J. Epi (1988) 128(2):261-267; Levine, A. et al., Ann Intern Med (1984) 100:7-13). It is clear that as the AIDS epidemic expands, non-Hodgkin's lymphoma will become a continually more important health problem in HIV-infected individuals. As treatment for the underlying HIV disease becomes more successful and as patients survive for longer periods of time in the absence of opportunistic infections, more cases of lymphoma will probably appear in this patient population.
The non-Hodgkin's lymphomas that develop in HIV-1 infected individuals fall into two main subcategories: the large cell lymphomas and the small non-cleaved cell Burkitt's lymphomas (Ziegler, J. et al., 1984, supra; Knowles, D. M. et al., Blood (1989) 73:792-799; Bermudez, M. et al.; Am J Med (1989) 86:71-76; Gill, P. et al., J Clin Oncol (1987) 5:1322-1328; Kaplan, L. D. et al, JAMA (1989) 261:719-724; Knowles, D. M. et al., Ann Intern Med (1988) 108:744-753; Lowenthal, D. A. et al., Cancer (1988)61:2325-2337). Both major classes of lymphoma are high grade neoplasms and are predominantly of B-cell origin (Ziegler, J. et al., 1984, supra.; Subar, M. et al., Blood (1988) 72:667-671.); however, T-cell lymphomas may also be increasing in frequency (Presant, C. A. et al., Cancer (1987) 60:1459-1461; Nasr, S. et al., Cancer (1988) 61:947-951; Herndier, B. et al., VII Intl Conference of Acquired Immunodeficiency Syndrome (AIDS), Florence, Italy, Jun. 16-21, 1991). In HIV disease lymphomas tend to be diffusely aggressive, with approximately 90% originating from B-cells and 5-10% derived from T-cells. Approximately one-half of the large cell lymphomas are herein termed "mixed immunophenotype" lymphomas as they contain a mixture of B-cells, T-cells, and macrophages. AIDS-associated non-Hodgkin's lymphomas are commonly characterized by their very high rates of extranodal (85-97%) (Kaplan, L. D. et al., JAMA (1989) 261:719-724; Burkes, R. L. et al., Arch Intern Med (1986) 146:913-915; Balasubramanyam, A. et al., Chest (1986) 90:243-246; Guarner, J. et al., Arch Pathol Lab Med (1987) 111:254-256; Kaplan, L. et al., Ann Intern Med (1989) 110:162; Friedman, S. L., Gastroenterol Clin North Am (1988) 17:465-486) and central nervous system involvement (35%) (Baumgartner, J. et al., J Neurosurg (1990) 73:206-211; Formenti, S. C. et al., Cancer (1989) 63:1101-1107; Ciricillo, S. et al., J Neurosurg (1990) 73:720-724), as well as their poor response to current chemotherapy protocols (Kaplan, L. D. et al., (1989) supra; Bermudez, M. et al., Am J Med (1989) 86:71-76; Gill, P. et al., J Clin Oncol (1987) 5:1322-1328; Urba, W. et al., Journal of the National Cancer Institute (1990) 10:29-37; Kaplan, L. D. et al., JCO (1991) 9(6):929-940).
Lymphomas, in general, are a heterogeneous group of malignancies. Their biologic behavior ranges from indolent, requiring no therapy, to aggressive malignancies with few long-term survivors. The behavior of lymphoma is influenced by the immune status of the host. The risk of B-cell lymphoma is dramatically increased in individuals with defects of cell-mediated immunity. The best characterized of these groups is immunosuppressed allograft recipients, whose risk of developing lymphoma is between 50 and 60 times that of the general population. These individuals develop a spectrum of lymphoproliferative diseases ranging from typical monoclonal immunoblastic lymphoma to an aggressive form of polyclonal lymphoproliferative disease (Frizzera, G. et al., Cancer Res (1981) 41:4262-4279; Hanto, D. W. et al., Cancer Res (1981) 41:4253-4261; Hanto, D. W. et al., Ann Surg (1983) 198:356-369) often associated with Epstein Barr Virus (Hanto, D. W. et al., (1981) supra; Penn, I., Transplant Proc (1983) 15 (suppl 1):S2790-S2797; Shearer, W. T. et al., N Engl J Med (1985) 312:1151-1159) infection. Clinically, lymphoma in these individuals presents aggressively at extranodal sites indicating a common feature between HIV-associated lymphomas and the molecular and clinical characteristics of the allograft-associated lymphomas.
The primary means of HIV lymphoma diagnosis remains microscopic examination of hematoxylin and eosin-stained sections from formalin-fixed tissue. Over time, pathologists have used clinical presentations, autopsy follow-up, and trial and error to develop histologic methods of diagnosing and categorizing cancer. Missing a histologic diagnosis of cancer or `over-calling` a cancer and subjecting a patient to cancer therapy are sufficient incentives for providing accurate diagnosis. Traditional histologic methods can be enhanced by phenotypic and, particularly, genotypic analyses of lymphomas where the discerned molecular changes of the affected tissue point to an alternative form of treatment.